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ABSTRACT

Background:

Coronary artery disease (CAD) is a leading cause of death throughout the world. CAD has been recognized among younger age group more frequently even in Nepal. The present study thus aims to estimate the serum apolipoprotein B (Apo B) and Apo A, and inflammatory biomarkers in young patients of acute myocardial infarction attending the tertiary care center of eastern Nepal.

Methodology:

This was a hospital-based cross-sectional study conducted from August 2014 to July 2015. Thirty-eight patients aged 15–45 years presented with an acute myocardial infarction were enrolled. Eleven risk factors were studied in the study population. The study population was further divided into two groups: Group A: 35 years of age or less and Group B: 36–45 years of age.

Results:

Majority of the subjects were hypertensive with the history of smoking and alcohol intake. Serum Apo B was significantly raised as compared to the Apo A in the study population with serum hsCRP and uric acid being significantly higher in Group B as compared to Group A patients.

Conclusion:

This study concludes that Apo B/Apo A-1 ratio is a better predictor of myocardial infarction in young adults as compared with the conventional lipid parameters and other biomarkers of inflammation (hsCRP and uric acid), respectively.

Keywords:

Introduction

Coronary artery disease (CAD) is a leading cause of death throughout the world [1]. Over 85% of morbidity and 80% of mortality from cardiovascular disease (CVD) occur in low- and middle-income countries [2]. Though, very few studies regarding prevalence have been carried out, it is still considered as one of the commonest admitted cases in major hospitals of Nepal. The prevalence of Coronary heart disease (CHD) in Dharan Municipality was found to be 5.6% [3]. CAD is gradually emerging as one of the major health challenges in Nepal. The rapid change in lifestyle, unhealthy habits (smoking, sedentary lifestyle, etc.), and economic development are considered to be responsible for the increase of CVD and CAD. Despite the decrease in CVD mortality in developed countries, a substantial increase has been experienced in developing countries. Hence, the large-scale epidemiological study was suggested to be carried out to determine the incidence and prevalence of CAD in Nepal to identify the magnitude of the problem and appropriate primary and secondary prevention strategies should be vigorously pursued [4].

Acute coronary syndrome (ACS) encompasses a range of disorders from unstable angina through non ST elevation to ST elevation [5]. Myocardial infarction is a leading cause of death in the world in both developed and developing countries. The South Asian countries like India, Pakistan, Bangladesh, Sri Lanka, and Nepal account for about a quarter of the world’s population and contribute the highest proportion of the burden for CVDs as compared with other regions in the globe [6]. Death claims mostly in the elderly population; in the US, 83% of Ischemic heart disease (IHD) deaths were in patients of more than 65 years of age [7]. Few studies done in Nepal had reported that the cases of myocardial infarction have doubled annually between 2001 and 2008 [8]. Moreover, patients suffering from CAD in this part of the world were of relatively younger age, i.e., about half of Myocardial Infarction (MI) occurred under the age of 50 years [9].

Apolipoproteins are proteins associated with lipids in lipoprotein particles which play an important role in lipoprotein metabolism, such as transport of these hydrophobic molecules in plasma aqueous medium, binding to specific receptors in cell surface to correctly direct lipids to target organs and body tissues, and activation or inhibition of enzymes involved in lipid metabolism [10]. Apolipoprotein A-I (Apo A-I) is the largest component of the high- density lipoprotein (HDL) particle [11], which plays a crucial role in reverse cholesterol transport and thus is considered to be anti-atherogenic [12]. Apolipoprotein B (Apo B) is the main functional protein associated with low-density lipoprotein (LDL) [13], and hence potentially atherogenic [12]. Various studies have been reported from different parts of the world reflecting the importance of Apo A and Apo B concentrations and their ratio as a predictor of risk factors in myocardial infarction.

Dyslipidemia, low Apo A-1, and high Apo B are widely accepted as the risk factors for CAD [12]. In contrast, the correlation has not been well established for myocardial infarction in young adults yet in Nepal. This study was undertaken to assess the risk factors of acute myocardial infarction in young adults and compare the difference in risk factors in patients of age group 15–35 years and 35–45 years.

Subjects and Methods

This is a hospital-based descriptive cross-sectional study conducted in B. P. Koirala Institute of Health Sciences, Dharan, Nepal. Thirty-seven patients of the age 15–45 years (young adults) were included in the study. The study participants were further divided into two groups, namely Group-A (15–35 years) and Group-B (36–45 years).

The diagnosis of MI was based on European Society of Cardiology criteria which includes a rise in biochemical marker troponin, symptoms of ischemia, ECG changes (ST-T changes or new left bundle branch block), development of pathological Q waves, imaging evidence of new loss of viable myocardium, or new regional wall motion abnormality [5].

The criteria for ST-T changes were; new ST-elevation at the J point in two contiguous leads with the cut-off points: ≥0.2 mV in men or ≥0.15 mV in women in leads V2–V3 and/or ≥0.1 mV in other leads. New horizontal or down sloping ST-depression ≥0.05 mV in two contiguous leads; and/or T-inversion ≥0.1 mV in two contiguous leads with prominent R wave or R/S ratio >1. Any Q wave in leads V2–V3 ≥0.02 seconds or QS complex in leads V2 and V3. Q wave ≥0.03 seconds and ≥0.1 mV deep or QS complex in leads I, II, aVL, aVF, or V4–V6 in any two leads of a contiguous lead grouping (I, aVL, V6; V4–V6; II, III, aVF). R wave ≥0.04 seconds in V1–V2 and R/S ≥1 with a concordant positive T wave in the absence of a conduction defect. All patients from 15 to 45 years of age presenting with first acute myocardial infarction were included. Patients with stable or unstable angina, or patients having old MI, and those having age less than 15 or above 45 were excluded from the study.

The risk factors studied were MI or sudden death before the age of 55 years in father or first-degree male relatives or in mother before the age of 65 years or other first-degree female relatives and currently smoking or left smoking in less than 3 months of the diagnosis. Patients were considered hypertensive if they were already on antihypertensive therapy or reports that had a blood pressure of more than 140/90 mmHg on two or more occasions. The patients were taken as diabetics if they were already taking treatment for diabetes or fasting blood sugar ≥126 mg/dl or random blood sugar ≥200 mg/dl.

Biochemical markers measured were Apo B/Apo A-1 ratio, hsCRP, and uric acid, respectively. Apo B/Apo A ratio was considered abnormal if it was more than 1.12 in females and more than 1 in males.

Serum Apo A and Apo B levels were measured by an immunoturbidimetric method using a Fully Automated Autoanalyzer (cobas c311 Autoanalyzer) with intra- and inter-assay %CV less than 5% and according to the procedure recommended by reagent manufacturer. Serum hsCRP level was estimated by the immunoturbidimetric method using a Fully Automated Autoanalyzer (cobas c311 Autoanalyzer) with intra- and inter-assay %CV less than 5%. Serum uric acid levels were measured by standardized enzymatic PAP method with uricase and peroxidase, in cobas c311 Autoanalyzer with intra- and inter-assay %CV less than 2.44% and according to the procedure recommended by the manufacturer.

Data were first checked for normality using the Kolmogorov–Smirnov Test. Student’s t-test was used for variables with normal distribution and the Mann–Whitney U test for the non-normally distributed variables. The Chi-square test was used for categorical variables, and correlations among the parameters were examined by Pearson’s and Spearman’s rho correlation according to the nature of the data. The calculations were performed using the statistical program SPSS for Windows Version 11.5 (Chicago Inc), with a p-value of <0.05 considered to be statistically significant. Receiver operating characteristic (ROC) plots and cut-off levels for maximal sensitivity and specificity were produced using the program MedCalc for PC (MedCalc Software, Belgium).

Results

The present study demonstrates that the mean age of the patient with myocardial infarction in young adults was 39.84 ± 4.79 with the majority of the patients being male. Among them, majority of the patients were hypertensive, diabetic, and had the history of smoking and alcohol intake. These findings had been illustrated in Table 1. Mean total cholesterol, LDL, and Triglyceride (TG) were higher and HDL was lower in Group B compared to Group A, respectively. Apo B/Apo A ratio was higher in Group B compared to Group A with hsCRP and uric acid also being higher in the same group as given in Tables 2 and 3, respectively. Pearson’s correlation depicts that Apo B/Apo A ratio is significantly correlated with the traditional lipid profile parameters, i.e., total cholesterol, triglycerides, and LDL, respectively (Table 4). ROC curve showed that the ratio of Apo B/Apo A has shown to be a better predictive marker compared to hsCRP in myocardial infarction in young adults (Figure 1).

Table. V depicting the sensitivity and specificity of the biochemical parameters in MI.

Parameters

AUC (95% CI)

Sensitivity

Specificity

Apo B/Apo A

0.60

60.7%

60%

hs CRP

0.48

42%

50%

Uric Acid

0.65

75%

50%

AUC = Area under Curve.

Discussion

Numerous research studies have been put forward to identify the novel risk factors for the prediction of the atherosclerotic process which leads to high incidence of CAD among the Nepalese Population. Apolipoproteins have been highlighted as the predictive risk factor for CAD since few years [14]. A close association of apolipoprotein metabolism with the development of atherosclerosis has been shown and Apo B/Apo A-1 ratio is being considered as a strong predictor of cardiovascular events than the conventional lipid parameters such as TG and LDL-C [15].

Acute STEMI in adults’ ≤35 years of age is uncommon [16]. Numerous mechanisms had been studied such as rupture of a vulnerable plaque or erosion of the endothelial layer, hypercoagulable state, coronary artery spasm, and inflammation, with atherosclerosis being the major cause [17]. Hyperbetalipoproteinemia in CAD patients had been nstrated by various western studies [18]. Increased levels of Apo B and decreased Apo A had been seen in patients with Acute Myocardial Infarction (AMI) and Apo B/Apo A-1 ratio had been reported to have a better predictive marker of underlying atherosclerosis compared to LDL-C and HDL-C, respectively [19].

Hypertension is a known risk factor of CVDs in older patients. 44.75% of the patients in the study were hypertensive which suggested that hypertension was not associated with myocardial infarction in the age group of 15–35 years as none of the patients were hypertensive. This was in contrast to the study done by Lin et al. [20], which concluded that hypertension was one of the independent predictors of myocardial infarction in young adults and was the most powerful risk factor of MI in young adults.

Type 2 Diabetes Mellitus is also considered to be a major risk factor of CVD in older patients. The study showed that 47% of the patients with MI were diabetic. This was parallel to the findings given by Murray et al. [1] in which type 2 diabetes mellitus was seen in about 28% of the patients.

Thirty-two percent of the patients in the present study had a family history of MI or sudden death which was similar to the result seen in a study done in India which showed a family history of CAD in 28.7% of the patients [21]. Genetic factors appeared to play an important role in acute myocardial infarction along with conventional and emerging risk factors [22].Alcohol consumption is an important risk factor for acute MI. In the present study, 53% of the patient had the history of alcohol intake. Binge drinking of alcohol had also been reported to be associated with the development of MI in young adults, though the mechanism is not clear [23]. A case-control study done in India showed that concomitant consumption of tobacco and alcohol was also significantly associated with AMI (p < 0.01 and p = 0.003, respectively) [22].

The present study intended to correlate the association between apolipoproteins (Apo A and Apo B) and other inflammatory biomarkers in young adults with myocardial infarction. The predictive value of Apo B/Apo A-1 ratio and traditional lipid parameters in the young patients with MI were also assessed.

Ratio of Apo B to Apo A-1 reflects the balance of cholesterol transport. Higher value of Apo-B to Apo A-1 ratio indicated higher cholesterol in the circulation, thereby suggested cholesterol’s likely deposition in the arterial wall. In contrast, in lower Apo-B/Apo A-1, there was reverse cholesterol transport and hence the other beneficial functions [24]. The Apo B/Apo A-I ratio indicated the balance between atherogenic and anti-atherogenic particles, the higher the value, the higher was the CV risk [25]. The present study showed higher Apo B/Apo A-1 (60.53%) of patients with myocardial infarction which was in accordance with the findings shown by Tamang et al. [26] in the Nepalese population, Goswami et. al. [24] in Indian population, and Kim et. al. [27] in Korean population, respectively.

The findings of the present study were in consensus with the findings of a large global heart study of risk factors for acute myocardial infarction in 52 countries which concluded that the Apo B/A-I ratio was the most important risk factor in all geographic regions. A study reported in 2001 by Wallidus et al. [25] showed that the Apo B/Apo A-1 ratio is of potentially greater value than LDL cholesterol for predicting risk for fatal MI in men and women on the basis of a study in 175,553 individuals recruited from screening programs.

Apart from apolipoproteins, the present study also assessed the newer risk factors like hsCRP and uric acid in AMI in young adults. Uric acid has been considered to be an established marker for ischemic heart disease. The present study found that 34.21% of the patients had a higher uric acid level. This was in accordance with the study done in England, which showed the association between uric acid and myocardial infarction with a strong association in younger age group compared to the older age group [28].

Inflammation plays a major role in atherothrombosis and measurement of novel inflammatory markers such as hsCRP is very helpful for detecting individuals at a high risk of plaque rupture [29]. The present study found raised hsCRP in 89.47% of the patients which was similar to the study done in various part of the world [30,31].

It is well known that IHD risk factors synergize the effect of each other, and the clustering of risk factors is important in causing premature CAD. The present study depicts 95% of the patients had three or more risk factors which were similar to the study done by Faisal et al. [32] in which 94% of patients had three or more risk factors. Thus, the risk of AMI increases with an increased number of risk factors, and hence, the patient develops AMI at an early age.

This study also demonstrated the diagnostic utility of Apo B/Apo A-1 ratio as a predictor in AMI in young patients compared with the other inflammatory biomarkers i.e., hsCRP and uric acid. Apo B/Apo A-1 had a superior diagnostic accuracy (Sensitivity—60.7%; Specificity—60%) compared to the other markers of inflammation. This was in parallel to the study reported by Goswami et al. [24]. The measurements of Apo B and Apo A-I has been standardized and is easily accomplished with an automated assay [33]. Furthermore, fasting samples is not needed for assays of apolipoproteins, which clearly was an advantage over traditional lipid ratios. Another advantage of the apolipoproteins is that they are the better predictors of CHD risk of patients who are under lipid-lowering treatment (vs. traditional lipid measures) [34].

Conclusion

The present study elaborates the use of Apo B/Apo A-1 ratio in AMI in young adults in a tertiary care center of eastern Nepal. Apo B/Apo A-1 ratio has emerged as a better predictor of myocardial infarction in young adults compared with the conventional lipid parameters (TG, Total Cholesterol (TC), LDL, and HDL) and other biomarkers of inflammation (hsCRP and uric acid), respectively.

Acknowledgment

The author would like to acknowledge Dr. Sahadeb Prasad Dhungana for his help and support during the sample collection and report writing and Dr. Surendra Uranw for his help in the statistical analysis.

List of abbreviations

AMI

Acute Myocardial Infarction

Apo A-I

Apolipoproteins A-I

Apo-B

Apolipoproteins B

CAD

Coronary artery disease

CHD

Coronary heart disease

CV

Cardiovascular risk

HDL-C

High Density Lipoprotein Cholesterol

IHD

Ischemic heart disease

LDL- C

Low Density Lipoprotein Cholesterol

TG

Triglyceride

Funding

None

Declaration of conflicting interests

None

Consent for publication

Informed consent was obtained from the patients

Ethical approval

This study has been approved by the Institutional Ethical Review Board, B.P. Koirala Institute of Health Sciences, Dharan, Nepal, on November 21, 2014, and the code is IERB/238/014.